Yohimbine is a food supplement that is also used to treat erectile dysfunction. It has recently been introduced as a probe drug to assess the activity of cytochrome P450 (CYP) 2D6. This in vitro study investigated possible substrate and inhibitor properties of yohimbine for drug transporters and inhibitor properties for CYPs to assess, whether yohimbine might be prone to drug-drug interactions. Inhibition of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptides (OATPs) and organic cation transporters (OCTs) was tested by using probe substrates and transporter-overexpressing cell lines. The potential substrate properties of yohimbine for P-gp and OCTs were tested in accumulation assays in different cell lines with and without overexpression of the respective transporter. Inhibition of CYPs was assessed by using luminogenic substrates. The interaction of yohimbine with OCTs was evaluated in silico using docking analyses. Yohimbine did not inhibit P-gp, BCRP, OATP 1B1, 1B3 and 2B1. It was described and characterised in vitro and in silico as a good substrate of OCT1-3 (Km between 3.7 and 6.2 μM) and a weak inhibitor of OCT2 and OCT3 with IC50 values in the upper micromolar range. Yohimbine potently inhibited CYP2D6 with an IC50 of 0.31 μM, weakly inhibited CYP1A2, CYP2C19, and CYP3A4, and did not inhibit CYP2B6. In conclusion, we have verified that yohimbine inhibits CYP2D6 and demonstrated that it is a substrate of OCT1, OCT2, and OCT3, a weak inhibitor of OCT2 and OCT3, but does not inhibit P-gp, BCRP, OATP1B1, OTP1B3, OATP2B1, and OCT1.

• Keywords
• Breast cancer resistance protein, Molecular docking, Organic anion transporting polypeptide, Organic cation transporters, P-glycoprotein, Yohimbine,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism   MeSH
• Isoenzymes metabolism   MeSH
• Drug Interactions MeSH
• Humans MeSH
• Neoplasm Proteins metabolism   antagonists & inhibitors   MeSH
• Organic Cation Transport Proteins * metabolism   chemistry   MeSH
• Molecular Docking Simulation MeSH
• Cytochrome P-450 Enzyme System * metabolism   MeSH
• Yohimbine * pharmacology   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ABCG2 protein, human MeSH Browser
• Isoenzymes MeSH
• Neoplasm Proteins MeSH
• Organic Cation Transport Proteins * MeSH
• Cytochrome P-450 Enzyme System * MeSH
• Yohimbine * MeSH

PI3K signaling pathway is crucial for a plethora of cellular processes and is extensively linked with tumorigenesis and chemo-/radioresistance. Although a number of small molecule inhibitors have been synthesized to control PI3K-mediated signaling, only a limited clinical success has been reached. Thus, the search for novel promising candidates is still ongoing. Herein, we present a novel series of N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides designed to simultaneously inhibit PI3K and DNA-PK activity. Compared to a commercial DNA-PK/PI3K inhibitor AZD7648, synthesized compounds generally exhibited markedly lower baseline cytotoxicity in all tested cell lines (MC38, B16F10, 4T1, CT26 and HEK-239). Through an array of biological experiments, we selected two most promising compounds, 2 and 6. While in cell-free conditions, 6 acted as a very efficient pan-PI3K and DNA-PK inhibitor, in physiological conditions, 2 performed better and acted as a potent chemosensitizer able to increase the amount of DNA double strand breaks induced by doxorubicin. This was plausibly due to its improved ability to accumulate in nuclei as evidenced by confocal analyses. Importantly, using P-gp overexpressing CT26 cells, we found that 2 is an efficient inhibitor of multidrug resistance (MDR) able to down-regulate expression of mRNA encoding MDR-driving proteins ABCB1A, ABCB1B and ABCC1. We also demonstrate that 2 can be simply loaded into lipid nanoparticles that retain its chemosensitizing properties. Taken together, the presented study provides a solid basis for a subsequent rational structure optimization towards new generation of multitarget inhibitors able to control crucial signaling pathways involved in tumorigenesis and drug resistance.

• Keywords
• Chemosensitization, DNA-Dependent protein kinase, Doxorubicin, Drug delivery, Multitarget inhibition, Phoshphoinositide-3-kinases inhibitors, Resistance,
• MeSH
• Drug Resistance, Neoplasm * drug effects   MeSH
• Phosphatidylinositol 3-Kinases metabolism   MeSH
• Phosphoinositide-3 Kinase Inhibitors * pharmacology   MeSH
• Protein Kinase Inhibitors * pharmacology   chemistry   chemical synthesis   MeSH
• Humans MeSH
• Drug Resistance, Multiple * drug effects   MeSH
• Molecular Structure MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 1 * antagonists & inhibitors   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• DNA-Activated Protein Kinase * antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Screening Assays, Antitumor MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phosphatidylinositol 3-Kinases MeSH
• Phosphoinositide-3 Kinase Inhibitors * MeSH
• Protein Kinase Inhibitors * MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 1 * MeSH
• DNA-Activated Protein Kinase * MeSH
• Antineoplastic Agents * MeSH

Elevated serum uric acid levels are the essential pathophysiology of gout. Although gout rarely develops in childhood, chronic persistent hyperuricemia can induce precipitation and deposition of sodium urate crystals, leading to the development of gout. Hyperuricemia is caused by increased uric acid production and/or decreased uric acid excretion capacity of the kidneys and/or intestinal tract. Increased production of uric acid, the final metabolite of purine, is associated with an increase of phosphoribosyl pyrophosphate, the key compound in the purine synthesis pathways, as observed in hypoxanthine-guanine phosphoribosyltransferase deficiency. Another mechanism for increased uric acid production is increased adenosine triphosphate consumption that is found in glycogen storage disease type I. On the other hand, in uromodulin-associated kidney disease, the accumulation of abnormal uromodulin in the kidneys leads to tubulointerstitial damage and fibrosis, and the ability to excrete uric acid is compromised, with reduced secretion and increased reabsorption in the proximal tubules. Decreased uric acid excretion from the kidneys or intestinal tract is also mediated by decreased function of the ATP-binding cassette subfamily G member 2, a urate transporter that acts in the urate secretion. This review summarizes the selected pathophysiological mechanisms underlying the genetic basis of hyperuricemia and gout in children, both in terms of purine metabolism and uric acid excretion.

• Keywords
• Glycogenosis, Gout, Hyperuricemia, Pediatric-onset, Urate transport, Uric acid overproduction, Uromodulin,
• MeSH
• Child MeSH
• Gout * genetics   etiology   epidemiology   MeSH
• Genetic Predisposition to Disease MeSH
• Hyperuricemia * genetics   complications   MeSH
• Uric Acid metabolism   blood   MeSH
• Humans MeSH
• Age of Onset MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Uric Acid MeSH

We report the identification of two pathogenic variants in the ABCG2 gene, encoding a urate exporter, in two probands (male and female) with severe familial gouty phenotypes and hyperuricemia. Clinico-genetic analyses identified p.I63YfsTer54 (rs565722112) and p.G74D (rs199976573) as potentially causal mutations; functional analyses demonstrated that these two variants are deficient in plasma membrane localization and functionally null. Our data show that dysfunctional variants in the ABCG2 gene are strong risk factors for hyperuricemia and gout in both males and females.

• Keywords
• ABCG2, Gout, Hyperuricemia, Urate transport,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 * genetics   metabolism   MeSH
• Gout * genetics   metabolism   pathology   MeSH
• Hyperuricemia * genetics   metabolism   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• Neoplasm Proteins * genetics   metabolism   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 * MeSH
• ABCG2 protein, human MeSH Browser
• Neoplasm Proteins * MeSH

Zosuquidar (LY335979) is a widely used experimental P-glycoprotein (P-gp) inhibitor, which is commended as very potent but also as very specific for P-gp. In this in vitro and in silico study, we demonstrated for the first time that zosuquidar also inhibits organic cation transporters (OCT) 1-3, albeit less potently than P-gp. This still has to be kept in mind when zosuquidar is used to inhibit cellular efflux of P-gp substrates that are concurrently transported into the cells by OCTs. To avoid interference in these assays, zosuquidar concentrations should be kept below 1 µM.

• Keywords
• LY335979, Metformin, Molecular docking, Organic cation transporters, P-glycoprotein, Zosuquidar,
• MeSH
• Quinolines * pharmacology   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 1 * antagonists & inhibitors   MeSH
• Organic Cation Transport Proteins * antagonists & inhibitors   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Quinolines * MeSH
• Dibenzocycloheptenes MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 1 * MeSH
• Organic Cation Transport Proteins * MeSH
• zosuquidar trihydrochloride MeSH Browser

Multidrug resistance (MDR) represents one of the major concerns in cancer therapy as it may cause reduced efficacy of chemotherapeutic drugs due to the overexpression of ABC transporters, particularly P-glycoprotein (P-gp). This study explores the potential of novel amphiphilic diblock (DB) copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide]-based copolymers (PHPMA) and poly(propylene oxide) (PPO) to overcome MDR mechanisms. The DB copolymers and their doxorubicin (Dox) conjugates significantly increased Dox accumulation in P-gp positive cells, markedly sensitizing them to Dox cytotoxic activity. The underlying mechanisms included depletion of intracellular ATP with subsequent inhibition of P-gp mediated drug efflux, an altered mitochondrial membrane potential, and increased ROS production. Moreover, the DB-Dox conjugates inhibited tumor growth in vivo more effectively compared to the corresponding PHPMA-based drug delivery system. Copolymers with additionally loaded PPO in the micelle core demonstrated superior efficacy in terms of P-gp inhibition, ATP depletion, and chemosensitizing effect in vitro, as well as antitumor activity in vivo. DB copolymers effectively depleted ATP levels both in vitro and in vivo using patient-derived xenograft (PDX) models, underscoring their capacity to enhance the effectiveness of standard chemotherapy and translational potential.

• Keywords
• Diblock copolymers, Drug delivery system, HPMA copolymer, Intracellular ATP depletion, Multidrug resistance, P-glycoprotein inhibition, PPO, Sensitization to chemotherapy,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Doxorubicin * administration & dosage   chemistry   therapeutic use   MeSH
• Humans MeSH
• Methacrylates chemistry   MeSH
• Micelles MeSH
• Drug Resistance, Multiple drug effects   MeSH
• Mice, Inbred BALB C MeSH
• Mice, Nude MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplasms drug therapy   metabolism   pathology   MeSH
• Drug Carriers * chemistry   MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 1 * metabolism   MeSH
• Polymers chemistry   MeSH
• Polypropylenes * chemistry   MeSH
• Propylene Glycols * chemistry   administration & dosage   MeSH
• Antibiotics, Antineoplastic * administration & dosage   chemistry   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Doxorubicin * MeSH
• Methacrylates MeSH
• Micelles MeSH
• Drug Carriers * MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 1 * MeSH
• Polymers MeSH
• polypropylene glycol MeSH Browser
• Polypropylenes * MeSH
• Propylene Glycols * MeSH
• Antibiotics, Antineoplastic * MeSH

The ABCB1 gene, encoding the ATP-dependent translocase ABCB1, plays a crucial role in the clearance of amyloid-beta (Aβ) peptides and the transport of cholesterol, implicating it in the pathogenesis of Alzheimer's disease. The study aims to investigate the association between polymorphisms in the ABCB1 gene and cognitive decline in individuals with mild cognitive impairment (MCI), particularly focusing on language function. A longitudinal cohort study involving 1 005 participants from the Czech Brain Aging Study was conducted. Participants included individuals with Alzheimer's disease, amnestic MCI, non-amnestic MCI, subjective cognitive decline, and healthy controls. Next-generation sequencing was utilized to analyze the entire ABCB1 gene. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests, including the Boston Naming Test and the semantic verbal fluency test. Ten ABCB1 polymorphisms (rs55912869, rs56243536, rs10225473, rs10274587, rs2235040, rs12720067, rs12334183, rs10260862, rs201620488, and rs28718458) were significantly associated with cognitive performance, particularly in language decline among amnestic MCI patients. In silico analyses revealed that some of these polymorphisms may affect the binding sites for transcription factors (HNF-3alpha, C/EBPβ, GR-alpha) and the generation of novel exonic splicing enhancers. Additionally, polymorphism rs55912869 was identified as a potential binding site for the microRNA hsa-mir-3163. Our findings highlight the significant role of ABCB1 polymorphisms in cognitive decline, particularly in language function, among individuals with amnestic MCI. These polymorphisms may influence gene expression and function through interactions with miRNAs, transcription factors, and alternative splicing mechanisms.

• Keywords
• ATP-binding cassette transporters, ATP-dependent translocase, Alzheimer’s disease, DNA polymorphisms, Language decline,
• MeSH
• Alzheimer Disease genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Cognitive Dysfunction * genetics   MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Neuropsychological Tests MeSH
• ATP Binding Cassette Transporter, Subfamily B genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• ABCB1 protein, human MeSH Browser
• ATP Binding Cassette Transporter, Subfamily B MeSH

Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320's absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.

• Keywords
• ABCB1, ABCC1, ABCG2, chalcone, colorectal carcinoma, drug efflux, expression, galectin-1, multidrug resistance, transporter,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism   MeSH
• ATP-Binding Cassette Transporters * metabolism   chemistry   genetics   MeSH
• Acridines * chemistry   pharmacology   MeSH
• Chalcone * pharmacology   chemistry   MeSH
• Chalcones * pharmacology   chemistry   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Colorectal Neoplasms metabolism   drug therapy   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• ATP Binding Cassette Transporter, Subfamily B metabolism   genetics   MeSH
• Cell Proliferation drug effects   MeSH
• Multidrug Resistance-Associated Protein 2 MeSH
• Multidrug Resistance-Associated Proteins metabolism   genetics   MeSH
• Antineoplastic Agents * pharmacology   chemistry   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Molecular Docking Simulation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ATP-Binding Cassette Transporters * MeSH
• ABCB1 protein, human MeSH Browser
• ABCC2 protein, human MeSH Browser
• Acridines * MeSH
• Chalcone * MeSH
• Chalcones * MeSH
• multidrug resistance-associated protein 1 MeSH Browser
• ATP Binding Cassette Transporter, Subfamily B MeSH
• Multidrug Resistance-Associated Protein 2 MeSH
• Multidrug Resistance-Associated Proteins MeSH
• Antineoplastic Agents * MeSH

Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant cancer cells. SCO-101 was found to inhibit the activity of breast cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving cancer treatment outcomes in patients with drug-resistant tumors.

• Keywords
• ABCG2, BCRP, SCO-101, UGT1A1, cancer multidrug resistance,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 * antagonists & inhibitors   metabolism   chemistry   MeSH
• Drug Resistance, Neoplasm * drug effects   MeSH
• Humans MeSH
• Drug Resistance, Multiple drug effects   MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins * antagonists & inhibitors   metabolism   chemistry   genetics   MeSH
• Neoplasms * drug therapy   metabolism   MeSH
• Antineoplastic Agents * pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester MeSH Browser
• ATP Binding Cassette Transporter, Subfamily G, Member 2 * MeSH
• ABCG2 protein, human MeSH Browser
• Diketopiperazines MeSH
• Heterocyclic Compounds, 4 or More Rings MeSH
• Neoplasm Proteins * MeSH
• Antineoplastic Agents * MeSH

Brassinosteroids (BRs) are steroidal phytohormones indispensable for plant growth, development, and responses to environmental stresses. The export of bioactive BRs to the apoplast is essential for BR signaling initiation, which requires binding of a BR molecule to the extracellular domains of the plasma membrane-localized receptor complex. We have previously shown that the Arabidopsis thaliana ATP-binding cassette (ABC) transporter ABCB19 functions as a BR exporter and, together with its close homolog ABCB1, positively regulates BR signaling. Here, we demonstrate that ABCB1 is another BR transporter. The ATP hydrolysis activity of ABCB1 can be stimulated by bioactive BRs, and its transport activity was confirmed in proteoliposomes and protoplasts. Structures of ABCB1 were determined in substrate-unbound (apo), brassinolide (BL)-bound, and ATP plus BL-bound states. In the BL-bound structure, BL is bound to the hydrophobic cavity formed by the transmembrane domain and triggers local conformational changes. Together, our data provide additional insights into ABC transporter-mediated BR export.

• Keywords
• ABCB1, Arabidopsis, brassinosteroids, signaling, structure, transport,
• MeSH
• ATP-Binding Cassette Transporters * metabolism   chemistry   genetics   MeSH
• Adenosine Triphosphate metabolism   MeSH
• Arabidopsis * metabolism   genetics   MeSH
• Biological Transport MeSH
• Brassinosteroids * metabolism   MeSH
• Arabidopsis Proteins * metabolism   chemistry   genetics   MeSH
• Steroids, Heterocyclic metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP-Binding Cassette Transporters * MeSH
• Adenosine Triphosphate MeSH
• brassinolide MeSH Browser
• Brassinosteroids * MeSH
• Arabidopsis Proteins * MeSH
• Steroids, Heterocyclic MeSH